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10.4 Placing of Devices on the Market in the EU 235
assessment can be based on the dossier for one representative device per generic
device group while for Class IIa and Class B assessment of a device representative
of a category of device is sucient.
Additional requirements apply to some categories of high-risk devices. In the case
of implantable Class III devices and Class IIb active devices intended to administer
and/or remove amedicine, the clinicalevaluation assessment report preparedby the
Notied Body must be submitted via the Commission to an expert panel for review
and provision of an opinion if appropriate. Consultation with relevant authorities
is also required for devices incorporating medicines, or tissues or cells of human
or animal origin. In the case of Class D IVDs, the performance of the device must
be veried by testing in designated EU reference laboratories. Should it be a new
type of device for which no Common Specication exists, the opinion of an expert
panel in relation to the performance evaluation report must be obtained. Similarly,
for companion diagnostics (IVDs that inuence the administration of medicines) or
Class B, C and D devices for self-testing and near-patient testing the assessment is
based on the device in question while additionally, companion diagnostics require
consultation with medicines regulators.
10.4.2.2 EU Type-Examination
EU type-examination is the alternative process that the manufacturer may use to
obtain independent verication that a device conforms to the general safety and per-
formance requirements, particularly where a certied quality management system
has not been applied to the design process. The manufacturer must submit an appli-
cation to the Notied Body, accompanied by the technical documentation on the
device and physical samples of the device. The Notied Body examines the docu-
mentation, tests the device samples, and if the design conforms to the requirements,
issues an EU type-examination certicate. This must be combinedwith either anEU
Quality Assurance Certicate (manufacture and nal inspection) or an EU product
verication certicate issued by the notied body in order for the manufacturer to
make the EU declaration of conformity.
10.4.2.3 Production Quality Assurance
Production quality assurance certication provides a means of assuring that manu-
factured devices will consistently meet the general safety and performance require-
ments attributed to the device. The manufacturer must lodge an application with a
Notied Body to have their system examined. The application must be accompanied
by information on the quality system and technical documentation on all relevant
EU-type-examined devices or representative devices in the case of Class IIa devices.
Following successful audit and review of the technical documentation the Notied
Body will issue an EU (production) quality assurance certicate. Requirements for
surveillance of the quality system are the same as apply to the Quality Management
Systems described earlier in Section 10.4.2.1.
10.4.2.4 EU Verification
EU verication relies on independent testing of all devices by or on behalf of the
Notied Body, who then issue an EU product verication certicate and allow their
236 10 Authorisation of Medical Devices
identication number tobe axed to each device. This is not a popular option due to
the costs involved but can be suitable for complex devices manufactured in low vol-
ume. The procedure is not capable of providing adequate assurance as to the sterility
of devices. Instead, assurance of sterility must be based on the application of a pro-
duction quality assurance system to the sterilisation process.
10.4.2.5 EU (Self) Declaration of Conformity
For low-risk devices (Class 1/Class A) the manufacturer may make a declaration of
conformity with the general safety and performance requirements on the basis of a
self-assessment, without any input from a Notied Body once they have drawn up
and reviewed the technical documentation specied in Annexes II and III of the reg-
ulations. In the case of Class I devices that are sterile, have a measuring function or
are re-usable surgical instruments, Notied Body involvement is required, to pro-
vide assurance as to the eectiveness of the sterilisation process, cleaning for re-use
or meteorological traceability of values as appropriate.
10.4.3 Technical Documentation
Assembling technical documentation that provides evidence of conformity with the
general safety and performance requirements is a fundamentalpart of all conformity
assessment procedures. The required contents of the technical documentation are
set out in Annexes II and III to the regulations. A summary of the headings and sam-
ple content of Annex II are summarised in Figure 10.10 while Annex III addresses
the requirements for technical documentation on post-market surveillance and in
particular, the post-marketing clinical/performance follow up (PMCF/PMPF) plan
and periodic safety update reporting (PSUR).
If technical documentation does not have to be submitted to a Notied Body, then
as a ‘living’ document it may be simpler to cross-reference to existing les rather
than assembling it into a single le. For example, data relating to the design could
just be cross-referenced to the existing development le/design history le, while
information on the quality system manufacturing or labelling could be referenced to
appropriate les. This facilitates keeping the le up to date, because for example if a
package insert was reviseddue to the additionof new languages, themaster labelling
les would just have to be updated, without having to also update a ‘central’ tech-
nical le. The technical documentation together with the declaration of conformity
and certicates issued by a Notied Body must be maintained at the disposal of the
Competent Authorities for a period of 10 years after manufacture of the last product.
Requests from Competent Authoritiesto view the technical documentation are most
likely to be triggered by problems in the market.
10.4.4 Labelling Requirements
The safety and performance requirements in Annex I provide reasonable detail
on the requirements for labelling of the dierent categories of medical devices.
Instructions for use must be supplied with all devices except for Class I and Class IIa
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10.4 Placing of Devices on the Market in the EU 237
ANNEX II TECHNICAL DOCUMENTATION
1. DEVICE DESCRIPTION AND SPECIFICATION, INCLUDING VARIANTS AND
ACCESSORIES
Trade name, unique device identier (UDI-DI), intended use/population, principle of
operation, risk class, etc.
2. INFORMATION TO BE SUPPLIED BY THE MANUFACTURER
Labels and instructions for use in relevant languages.
3. DESIGN AND MANUFACTURING INFORMATION
Information on design stages, information on manufacturing process, specications,
nal testing, manufacturing locations and suppliers.
4. GENERAL SAFETY AND PERFORMANCE REQUIREMENTS
Identication of applicable general safety and performance requirements, relevant
harmonised standards or common specications and methods used to demonstrate
compliance.
5. BENEFIT–RISK ANALYSIS AND RISK MANAGEMENT
The benet–risk analysis and solutions adopted for risk management.
6. PRODUCT VERIFICATION AND VALIDATION
Results and critical analyses of all verications and validation tests, analytical perfor-
mance (IVDs), clinical/performance evaluation report, post-market clinical follow-up
plan and evaluation.
Figure 10.10 Annex II Technical Documentation headings.
devices that can be used safely without accompanying guidance. The instructions
for use may be provided electronically provided the user can access them, and
the instructions need only be provided once to sites using multiple devices. In
general, the labelling should focus on ensuring that the device is used safely and
properly and where appropriate should address aspects such as intended use,
handling and storage, warnings and precautions, principles of the device and
operating instructions, expected performances and limitations. Labelling must be
in the national languages of the Member States. The use of symbols in accordance
with harmonised standard EN ISO 15223-1:2021, Medical devices – Symbols to
be used with information to be supplied by the manufacturer – Part 1: General
requirements is encouraged to overcome the diculties of trying to t multiple
languages on a device label. Examples of common symbols are illustrated in
Figure 10.11. The labelling must also bear the CE mark of conformity as previ-
ously illustrated in Figure 9.2. Where applicable, this must be accompanied by
the identication number of the Notied Body responsible for performing the
tasks required under the dierent conformity assessment procedures. Finally,
the labels must bear a Unique Device Identier (UDI) in a form that allows
automatic identication and data capture (AIDC) such as a bar-code or radio
frequency identication (RFID). The UDI is a series of numeric or alphanumeric
characters that is created through a globally accepted device identication and
coding standard and is comprised two elements; a UDI-DI which is assigned to
an individual device type/model and a UDI-PI which allows identication of the
specic unit of device production by serial number, lot number, or other appropriate
identier.
238 10 Authorisation of Medical Devices
Symbol Meaning Symbol Meaning
Do Not Reuse Sterile + method of sterilisation
Use by Temperature limitation
Batch number or lot number Serial Number
Date of manufacture Catalogue number
Attention, see instructions for use Consult instructions for use
Manufacturer Authorised representative
In vitro diagnostic medical device For performance evaluation
Number of tests
Figure 10.11 Symbols used on medical devices.
10.4.5 Registration of Economic Operators and Devices
Before placing a device on the market, manufacturers, authorised representatives
and importers must submit information electronically via EUDAMED. This will
include information on the identity of economic operator such as their name,
address and role, and information identifying the device(s) that they wish to place
on the market including the UDI-DI, risk class, Notied Body certicates and
Member States where the device will be marketed.
As a preliminary step in the process, the relevant Competent Authority will obtain
a single registration number (SRN) from EUDAMED and issue it to the economic
operator. This SRN enables the economic operator to interact with EUDAMED and
is also required when registering a device with an UDI-DI that can be submitted to a
UDI database or requestingNotied Bodies to conduct conformity assessments i.e. A
SRN is required to register a device with an UDI-DI and the UDI-DI isrequired when
applying to a NotiedBody for a conformityassessment. The economic operatorsare
required to keep the information in the databases up to date so that all concerned
actors can quickly identify and determine the status of any device.
10.5 Placing of Devices on the Market in the US
As mentioned in the previous chapter, device classication is central to determin-
ing the regulatory path to market for a device in the US. Most Class I and a few
Class II devices are exempt from any device-specic registration requirements. To
verify this, the manufacturer just needs to consult the database of existing devices,
identify an equivalent device and check that it is exempt from a pre-market noti-
cation requirement. If this is conrmed, then all that is required is that the manu-
facturer registers their establishment with the FDA, complies with applicable QSR
good manufacturing practices, labels the devices in accordance with the regulations
and undertakes to report adverse events to the FDA. All other devices will have to
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10.5 Placing of Devices on the Market in the US 239
go through a pre-market approval (PMA) procedure the case of the vast majority
of Class III devices or a less arduous 510(k) pre-market notication process in all
other cases i.e. mainly the Class I and Class II devices that are subject to pre-market
notication requirements.
10.5.1 510(k) Pre-market Notification
The 510(k) pre-market notication process is not as onerous as the PMA procedure
as clearance to market a device is not based on an assessment of the safety and
eectiveness of the particular device in question. Instead, devices can be cleared
on the basis that they are substantially equivalent to existing devices that have been
recognised as safe and eective, or that they conform to specic device standards
promulgated or recognised by the FDA. There are four procedural variations to the
510(k) notication process.
10.5.2 Traditional 510(k)
Traditional 510(k) notications are based on making a declaration of substantial
equivalence to an existing device. This can be either a device that was on the
market before the introduction of the medical device regulations in 1976 and
came under the scrutiny of classication panels at that stage, or devices that were
subsequently cleared using the 510(k) procedure. Identication of a suitable refer-
ence or ‘predicate’ device can be a crucial step when embarking on this approach.
The two pillars of substantial equivalence are ‘intended use’ and ‘technological
characteristics’. However, the two devices do not have to be identical, and a degree
of exibility is tolerated particularly with regard to methodology, where technical
advances could mean that the new device is superior to the predicate device in
terms of reliability, safety or eectiveness. If there is doubt as to the suitability of
a predicate device the FDA Oce of Device Evaluation may be consulted. The
manufacturer must then collect data that demonstrates the equivalence of the
new device to the predicate device. This will usually require some level of direct
comparison of performance of the two devices, whether it be a laboratory, eld trial
or clinical investigation.
10.5.3 Abbreviated 510(k)
An abbreviated 510(k) is basedon making a declaration of conformitytoa recognised
standard, special control, or specic FDA guidance. Again, the manufacturer must
provide test data in support of this assertion.
10.5.4 Special 510(k)
If a manufacturer has modied their own device, they can avail of a special 510(k)
procedure for declaring substantial equivalence to their existing device, provided
the intended use or the basic technology has not changed. They must apply design
240 10 Authorisation of Medical Devices
controls and risk analysis to the development process, but the advantage is that they
can receive a faster review process.
10.5.5 De Novo 510(k)
If a manufacturer has developed a new device for which no suitable predicate device
exists, they may be able to use a de novo 510(k) notication procedure. This is not
a common approach, as new innovative devices will tend to be viewed as Class III
devices requiring PMA. However, if the manufacturer can show that the level of risk
does not warrant placing it in the higher risk category, they may petition the FDA to
have it reviewed through the de novo 510(k) procedure.
10.5.6 Notification and Review Procedures
510(k) notications must be submitted electronically to the CDRH, except for some
devices that are regulated by CBER or CDER. The section headings recommended
by the FDA for a traditional or abbreviated 510(k) submission are outlined in
Figure 10.12 – all sections should be included even though some may not be
applicable depending on the device. The FDA are allowed 90 days to review a
Traditional or Abbreviated 510(k) notication and just 30 days for a Special 510(k).
With the introduction of the Medical Device User Fee and Modernization Act
of 2002, provision was made for the participation of third-party organisations
in the review process. This represents a partial adoption of in the concept of
Notied Bodies, which prevails in Europe. The FDA have accredited a number
of commercial organisations to conduct primary 510(k) reviews of 670 types of
devices. The FDA must then give a nal determination within 30days of receipt
of the recommendation of a third-party reviewer. Because they are commercial,
third-party reviewers will seek to oer faster review times in return for their review
fee. If using a third-party reviewer, the FDA user fee does not apply. The outcome
of a successful 510(k) notication is a letter from the FDA clearing the device for
commercial sale.
10.5.7 Pre-market Approval (PMA)
The PMA process is a considerably more complex procedure, as the FDA can only
grant marketing approval on the basis of an assessment of the actual safety and eec-
tiveness of the device in question. Thus, it is similar to a drug application, in that the
submission must contain a detailed manufacturing section describing the methods
for production and testing of the device, together with extensive data to substanti-
ate its safety and eectiveness. Whereas a 510(k) application may be cleared on the
basis of limited or no clinical data, a PMA requires substantial clinical investigation
data. The main requirements of a PMA submission are outlined in Figure 10.13. It
is advised to consult with the FDA in advance of nalising a PMA strategy if there is
any uncertainty about required data, particularly in the case of signicantly innova-
tive devices. The FDA may refer to an advisory council in such circumstances. Once
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10.5 Placing of Devices on the Market in the US 241
(1) Medical Device User Fee Cover Sheet (Form FDA 3601)
conrms payment of user fees
(2) Center for Devices and Radiological Health (CDRH) Premarket Review
Submission Cover Sheet (Form FDA 3514)
Captures general administrative information
(3) 510(k) Cover Letter
Provides a descriptive overview of the submission
(4) Indications for Use Statement (Form FDA 3881)
(5) 510(k) Summary or 510(k) Statement
A summary that will be made available to the public or a statement committing to
provide information on request
(6) Truthful and Accuracy Statement
A required statement certifying that all information submitted in the 510(k)istruthful
and accurate and that no material fact has been omitted
(7) Class III Summary and Certication
Relevant for submissions based on predicate Class III devices that have not been
subject to pre-market approval
(8) Financial Certication or Disclosure Statement
In relation to any clinical investigations to assure objectivity
(9) Declarations of Conformity and Summary Reports
(10) Device Description
(11) Executive Summary/Predicate Comparison
(12) Substantial Equivalence Discussion
(13) Proposed Labeling
Includes labels and instructions for use
(14) Sterilization and Shelf Life
(15) Biocompatibility
(16) Software
(17) Electromagnetic Compatibility and Electrical Safety
(18) Performance Testing – Bench
(19) Performance Testing – Animal
(20) Performance Testing – Clinical
Figure 10.12 Recommended sections of a traditional or abbreviated 510 K submission.
a submission is electronically received, it will go through a screening procedure to
check that it is completefor ling. A ling decision must bemade within 45 days. The
FDA is allowed 180 days to review and come to a decision on the submission. This
usually results in the issue of an approvable letter, which will just identify remain-
ing minor issues that need to be resolved for the FDA to issue an approval order, or
an order denying approval, if the FDA nds major deciencies in the submission.
As part of an approval order, the FDA may impose additional requirements such as
batch testing, or additional labelling requirements.
10.5.8 Changes to a PMA-Approved Device
Changes to an approved device that could aect its safety or eectiveness must be
submitted to the FDA as a supplemental application. These include changes to the
242 10 Authorisation of Medical Devices
1. Name & Address of Applicant
2. Table of Contents
3. Summary
Including indications for use, device description, alternative practices and procedures
currently available for the condition, marketing history (US or foreign) non-clinical
laboratory studies, clinical investigations and overall conclusions
4. Device description & Manufacture
Detailed drawings and description of device and methods used for manufacture and
control of the device.
5. Reference to Standards
Reference to standards for radiation protection and any other appropriate voluntary
standards relating to safety or eectiveness
6. Technical Sections
Non-clinical laboratory studies used to investigate microbiological, toxicological,
immunological, biocompatibility, stress, wear,shelf life, and other characteristicsof the
device
Data from clinical investigations on human subjects, plus statements as regards inves-
tigators, IRB’s and informed consent.
7. Single Clinical Investigation Justication
Information to justify reliance on a single clinical investigation, where applicable.
8. Bibliography
Relevant published reports and commentary
9. Device Samples (on request)
Provide samples of the device or a location where they may be tested by the FDA
10. Copies of Labelling
Labels, instructions for use, user manuals, etc.
11. Environmental Assessment
Assessment or declaration of exclusion from requirement
12. Financial Disclosure
Declarations of investigator’s nancial interests if any
13. Information concerning uses in pediatric patients
If available
Figure 10.13 Required content of a PMA application.
indications for use, changes to the labelling, packaging or sterilisation procedures,
new manufacturing or packaging sites, changes to the device or its specications
and alterations to its shelf life, if not based on a protocol agreed with the FDA. The
procedure for submission and review of a supplement are the same as for the initial
PMA, but in practice are likely to be faster because of their limited content. Minor
changes that enhance device safety or just make editorial corrections to labelling
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10.6 Chapter Review 243
may be introduced without prior approval, provided the changes are notied to the
FDA as part of periodic reports.
10.5.9 Humanitarian Use Devices (HUDs)
Similar to Orphan drug provisions, a device may be designated as a Humanitarian
Use Device (HUD) if it is intended to diagnose or treat a rare disease or condition
aecting less than 4000 US suerers. Applications for HUD status must be sub-
mitted to the Oce for Orphan Products Development, together with information
supporting the applications. A decision as to status will be made within 45 days. The
advantage of HUD status is that permission to market the device may be granted
on the basis of a Humanitarian Device Exemption (HDE) application, which does
not require the sponsor to submit comprehensive data as to the eectiveness of the
device. The permitted review times are shorter at 30 days for a ling decision and
75 days for an evaluation decision.
10.5.10 Labelling of Devices
General labelling requirements for devices are set out in 21 CFR 801. These include
the name and place of business of the manufacturer, packer or distributor, text sizes,
sucient instructions to enable the device to be used correctly, and information on
quantity per package, where applicable. This part also contains labelling require-
ments for particular typesof devices. For example, devices available only on prescrip-
tion should bear the statement, ‘Caution: Federal law restricts this device to sale by
or on the order of a ____’, the blank to be lled with the word ‘physician’, ‘dentist’,
‘veterinarian’ or other licensed professional. Specic requirements for the labelling
of in vitro diagnostic reagents may be found in 21 CFR 809. Devices approved under
an HDE must bear the statement, ‘Humanitarian Device. Authorized by Federal law
for use inthe [treatment or diagnosis] of [specify diseaseor condition]. The eective-
ness of this device for this use has not been demonstrated’.
10.6 Chapter Review
Although there is signicant dierence in the detail, the regulatory requirements
for evaluation and marketing authorisation of devices in Europe and the US both
reect a tiered response in relation to risk. This is illustrated in Table 10.3. In
Europe, conformity assessment is the responsibility of Notied Bodies, except for
low-risk devices where the manufacturer can perform the assessment. The Compe-
tent Authorities are only likely to get involved should problems be encountered in
the market place. In the US, although third part review is now possible for lower
risk devices, ultimate responsibility for market clearance or approval rests with
the FDA.
244 10 Authorisation of Medical Devices
Table 10.3 Overview of requirements vs. risk according to EU and US regulations.
EU requirements overview
Risk Clinical data
Authorisation
of clinical
investigations
Instructions
for use
Conformity
assessment
procedure
High (III) Specic Clinical
Investigations
expected
10 + 45 days for
approval by CA
Required Notied Body
certication of
specic device
(type or design)
Moderate (II) Clinical
evaluation of
existing clinical
data may be
sucient
10 + 45 days for
approval by CA
unless non-
implantable
Not required, if
can be used
safely (except
IVD’s)
Notied Body
involvement
Low (I) Clinical
evaluation may
justify exclusion
of clinical data
Proceed once
10-day
validation
window elapsed
Not required, if
can be used
safely, (except
IVD’s)
Self assessment
by manufacturer
US requirements overview
Risk class
Device
evaluation
Quality system
regulations
Marketing
authorisation
III IDE Full QSR PMA
II Abbreviated IDE possible Full QSR 510(k)
I May be IDE exempt QSR without design control Generally 510(k) exempt
10.7 Further Reading
European Regulations and Associated Guidance
https://health.ec.europa.eu/medical-devices-sector/new-regulations/guidance-mdcg-
endorsed-documents-and-other-guidance_en
US Code of Federal Regulations
Labelling 21 CFR Parts 801 & 809
Pre market Notication – 21 CFR Part 807, subpart E
Investigational Device Exemptions – 21 CFR Part 812
Pre market approval – 21 CFR Part 814
Quality System Regulations – 21 CFR Part 820
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